This is a renewal application for years 36 to 40 of a laboratory-based, interdisciplinary Program Project Grant, Molecular Basis of Viral and Cellular Transformation. For the last 15 years, this grant has been led by Daniel DiMaio, M.D., Ph.D., Waldemar Von Zedtwitz Professor of Genetics, and he continues as Principal Investigator. He is joined by three other project leaders: George Miller, Joan Steitz, and Joann Sweasy. All four project leaders have independent grant support from the NIH and have made major contributions to our understanding of virology and cell transformation. This Program seeks to achieve molecular understanding of the impact of viral and cellular gene products on cell transformation, because such understanding will provide insight into the genesis of cancer in humans and may suggest new approaches to therapy. In the past funding period, these same four project leaders participated in the Program, which resulted in 49 published papers, 37 of which are in top, peer-reviewed journals. These investigators will carry out five innovative, collaborative projects studying the molecular mechanisms by which viral and cellular gene products induce and maintain cellular transformation. Dr. Miller will study the switch from latency to lytic growth of Epstein-Barr virus, a major human carcinogen. Dr. DiMaio will study cellular senescence induced by repression of human papillomavirus oncogenes in cervical cancer cells, focusing on the molecular basis of the irreversible nature of senescence and on the role of microRNAs in senescence. In a separate project, he will determine the role of DNAJ proteins in SV40 infection. Dr. Steitz will study the role of tumor virus-encoded small RNAs in cell transformation. Dr. Sweasy will study the ability of cancer-associated DNA polymerase beta mutants to induce cellular transformation, with a focus on truncation mutants, animal models of carcinogenesis, and cooperation with human papillomavirus oncogenes. These projects will be supported by a small Administrative Core and an expanded Scientific Core. Several mechanisms are in place to ensure the cohesion of the program, including monthly meetings of the project leaders, an annual retreat, and boards of distinguished external and internal advisors to provide guidance and advice.